Animal and human studies have linked diabetes or hyperglycemia in the acute phase of ischemic stroke to worsening of clinical outcomes. Although a host of possibilities including increased oxidative stress have been suggested, the cellular and molecular mechanisms for this worsening in the setting of hyperglycemia remain elusive. We hypothesize that increased activation of Ca2+permeable acid sensing ion channels (ASICs) plays an important role in increased brain injury associated with diabetic patients during ischemia based on the following arguments and preliminary data: (1) Acidosis is a common feature of brain ischemia particularly in diabetic patients. Brain pH drops to 6.5 following ischemia in non-diabetic conditions but can drop to below 6.0 in diabetic or hyperglycemic conditions; (2) Acidosis activates Ca2+permeable ASICs in brain neurons in a pH dependent manner; (3) Activation of these channels plays an important role in acidosis-mediated glutamate independent neuronal injury associated with brain ischemia; (4) In addition, and central to this application, our preliminary studies demonstrate that deprivation of glucose (as expected in the affected brain region undergoing ischemia) further potentiates the activity of these channels and that the degree of potentiation is more dramatic if glucose deprivation is preceded by hyperglycemia, a condition pertinent to diabetic patients. Using a combination of electrophysiology, fluorescent imaging, ASIC knockout mice, in vitro and in vivo ischemia and diabetes models, our objective is to rigorously test the role of Ca2+ permeable ASICs in the increased sensitivity of hyperglycemic rats/mice to ischemic brain injury. Results achieved from these studies will provide a new mechanism for increased neuronal injury associated with diabetic and hyperglycemic patients, and will ultimately contribute to the development of novel neuroprotective strategies for these stroke patients, which is currently lacking.